tbuckley/cabot-search huggingface dataset:
MODL-19. Exploiting DNA damage response inhibitors to enhance radiation efficacy in medulloblastoma models
Authors: Hetal Dholaria, Jessica Buck, Hilary Hii, Brooke Carline, Jacob Bryne, Mani Kuchibhotla, Jessica Lawler, Gilbert Porter, Jacqueline Whitehouse, Meegan Howlett, Nick Gottardo, Raelene Endersby
Journal: Neuro-Oncology (2022)

Abstract Despite treatment intensification, survival for certain high-risk subgroups of medulloblastoma (MB) such as p53 mutant SHH (SHHa) and MYC amplified Group 3 (Gr3) have remained dismal. Recently, the use of Carboplatin as radiosensitiser with craniospinal irradiation (CSI) has shown survival benefit in children with Gr3 MB. However, there is an ongoing need to discover newer, non-chemo radiosensitisers which have minimal toxicity and unequivocal benefit in high-risk MB. Radiation is a potent inducer of DNA damage in cancer cells. CHK1/2, ATR, and WEE1 kinases are critical regulators of the DNA damage response (DDR). We hypothesised that inhibition of these kinases may enhance radiation-induced cytotoxicity in MB. We utilised small-animal radiotherapy platform to deliver CSI to MB-tumour-bearing mice that closely mimic clinical settings. Here we demonstrate systematic preclinical evaluation of DDR inhibitors (DDRi) as radiosensitiser in MB models. In vitro treatment of Gr3 MB cell lines with either CHK1/2 inhibitor (CHKi, Prexasertib, AZD7762), ATR inhibitor (ATRi, AZD6738), or WEE1 inhibitor (WEE1i, AZD1775) along with radiation ceased post-radiation cell cycle arrest, prohibiting DNA repair, and increasing apoptosis. The combination also reduced the colony-forming ability of MB cells post-irradiation. In vivo, CSI and DDRi, each induced modest apoptosis in orthotopically-implanted high-risk MB mice. When these models were treated with CHKi+CSI, ATRi+CSI or WEE1i+CSI, the effect was cumulative. Importantly, addition of DDRi to CSI significantly prolonged the survival of MB-bearing mice compared to CSI alone. Here we also explored strategy of “vertical blockade” by simultaneous use of CHKi and WEE1i which when combined with CSI also prolonged survival in MB-bearing mice. Additionally, we evaluated various regimens to best deliver these novel agents with CSI, maximising effect and minimising toxicity. Our study opens up new realms of radiosensitisation with the use of DDRi in paediatric medulloblastoma and provides robust preclinical evidence for clinical translation.
MODL-12.<i>Ex vivo</i> model identifies druggable vulnerabilities in medulloblastoma
Authors: Alexandre Gries, Davide Romanino, Karthiga Santhana Kumar, Ana S Guerreiro Stücklin, Michael A Grotzer, Martin Baumgartner
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant brain tumour in children and long-term sequelae in survivors caused by the harsh, non-targeted treatments is common. Current screening protocols for the detection of novel druggable vulnerabilities rely on 2D and 3D cell culture systems using established or primary tumour cells. However, these assays do neither provide the cellular, chemical and biophysical context of the tissue, nor reveal drug effects on the invasive behavior of the tumour cells. To overcome these limitations, we have established ex vivo Organotypic Cerebellum Slice Co-culture (OCSC) models for SHH and group 3 MB tumours, which provide spatio-temporal insights in the growth and dissemination behaviour of the tumour cells. OCSCs represent an excellent translational model for patient sample profiling, drug testing, and microenvironmental or explorative target identification studies in a physiologically relevant tissue context. We found that the AURKB inhibitor Barasertib (AZD-1152), which was ineffective to reduce ONS-76 cell invasion in vitro, effectively reduced tumour volume and proliferation of these SHH tumour cells in the tissue context. The AURKB inhibitor thus displays higher efficacy ex vivo, indicating an impact of the microenvironment on its functional activity. We further validated tumour suppressive activity of AURKB inhibition with Barasertib at low nanomolar concentration or with siRNA-mediated depletion of AURKB in Grp3 MB tumour cells and in primary tumour cells ex vivo, thereby confirming the therapeutic potential of AURKB inhibition against MB progression. We furthermore found that the combination of AURKB inhibition with irradiation or with the SRC inhibitor Dasatinib, lead to a near complete eradication of the tumour cells. Thus, OCSCs are a clinically relevant model where tumour material can be efficiently tested for drug sensitivities, which allowed us to identify AURKB inhibition as an effective treatment against tissue invasive MB.
Management and outcomes of non-muscle invasive bladder recurrence after complete response to trimodality therapy for muscle-invasive bladder cancer: A monocentric experience
Authors: E. Debedde, M. Felber, J. Coelho, E. Fabiano, C. Durdux, M-O. Timsit, A. Méjean, F. Audenet
Journal: European Urology (2022)
LGG-21. Durability of response to targeted therapies in pediatric low-grade gliomas: A multi-institution retrospective review
Authors: Evan Cantor, Sneha Chaturvedi, Stephanie Reiners, Andrea Ogle, Ashley Meyer, Andrew Cluster, Nicole M Brossier, Hetal Dholaria, Dinisha Govender, Sumanth Nagabushan, Johnathan Schwartz, Mohamed S Abdelbaki, Pournima Navalkele, Margaret Shatara
Journal: Neuro-Oncology (2022)

Abstract Background: The discovery of the driving oncogenic alterations in pediatric low-grade gliomas (pLGGs) has shifted our focus towards management with targeted therapies, especially in relapsing or progressive disease. Limited data is available on the durability of response to targeted therapy in pLGGs once the therapy has ceased. Methods: Multi-institutional retrospective chart review of patients with pLGGs younger than 25 years, between 2010-2021, was undertaken to evaluate the durability of response to targeted therapy and determine risk factors associated with disease progression after cessation of therapy. Results: Current analysis included 18 patients from two centers. Seven (39%) had neurofibromatosis type-1 (NF-1). Diagnoses included: optic pathway glioma (OPG) (6/18, 33%), pilocytic astrocytoma (8/18, 44%), diffuse fibrillary astrocytoma (1/18), ganglioglioma (1/18), glioneural neoplasm (2/18). Sixteen patients received at least one prior line of chemotherapy (range 1-5). Targeted agents included trametinib (50%), selumetinib (5%), binimetinib (22%), vemurafenib (11%) and everolimus (11%). Median time on therapy was 351 days (range 29-979 days). All, but one patient had residual intracranial findings at the end of therapy: eight patients (44%) had stable disease, while ten required additional therapy; 50% were NF-1 patients with OPG. Median time to progression was 203 days (range 29-615 days). Of those who did not require any additional therapies, 50% had suprasellar tumors. Genomic data was available for twelve patients; BRAF-KIAA1549 fusion was the most common genomic alteration. Others included mutations in KRAS, BRAF (V600E), PTPN11, SOX6-RAF1 fusion, NF-1, and a patient with FGFR1, KMT2C, and PTPN11 alterations. Conclusion: Preliminary analysis demonstrates that despite initial response, the majority of patients required additional line of therapy. Patients with NF-1 and OPGs tend to progress after discontinuing therapy, while suprasellar non-NF1 pLGGs tend to develop sustained response to targeted therapies. Additional multi-institutional analysis is underway and will be presented at the meeting.
Trends in low-value oncology care during the COVID-19 pandemic.
Authors: Ravi Bharat Parikh, Yasin Civelek, Pelin Ozluk, David Joseph Debono, Michael Jordan Fisch, Gosia Sylwestrzak, Justin E. Bekelman, Aaron L Schwartz
Journal: Journal of Clinical Oncology (2022)

6594 Background: Low-value services, which provide minimal patient benefit while entailing costs and risks, are prevalent in cancer care. Shifts in cancer care delivery during the COVID-19 pandemic to minimize exposure provided opportunities for health systems and clinicians to prioritize higher-value over low-value oncology services. Methods: In this retrospective cohort study, we investigated the association between the COVID-19 pandemic period and low-value cancer care practices using administrative claims from the HealthCore Integrated Research Environment, consisting of ̃65 million members managed by 14 health plans across the US. We identified commercial or Medicare Advantage members diagnosed with breast, colorectal, or lung cancer between January 2015 and March 2021. Low-value cancer care practices were identified from peer-reviewed medical literature, including ASCO and ASTRO Choosing Wisely campaigns and evidence-based pathways. Five low-value practices were studied: (1) conventional fractionation instead of hypofractionation for early-stage breast cancer; (2) off-pathway systemic therapy; (3) non-guideline-based antiemetic use for minimal-, low-, or moderate-to-high-risk chemotherapies; (4) Positron Emission Tomography/Computed Tomography (PET/CT) instead of conventional CT for staging; and (5) aggressive end-of-life care (chemotherapy ≤14 days, multiple emergency department visits ≤30 days, ICU utilization ≤30 days, hospice initiation ≤3 days, and/or no hospice before death). We used linear probability models to evaluate the association between the COVID-19 period (March to December 2020) and the 5 outcomes, adjusting for patient, facility, geographic and temporal characteristics. Results: Among 204,581 members (mean age 63.1, 139,488 [68.1%] female), 83,593 (40.8%) had breast cancer, 56,373 (27.5%) had colon cancer, and 64,615 (31.5%) had lung cancer. Rates of low-value care were similar in pre-COVID vs. COVID periods: conventional radiotherapy: 22.1% vs. 9.4%; off-pathway systemic therapy: 36.7% vs. 43.2%; non-guideline-based antiemetics: 61.2% vs. 58.1%; PET/CT imaging: 39.9% vs. 41.3%; aggressive end-of-life care: 75.8% vs. 73.3%. In adjusted analyses, the COVID-19 period was associated with no changes in off-pathway therapy (adjusted percentage point difference [aPPD] 0.82, SD 0.08, p = 0.33), PET/CT imaging (aPPD 0.10, SD 0.005, p = 0.83), and aggressive end-of-life care (aPPD 2.71, SD 0.02, p = 0.16). Small changes in conventional radiotherapy (aPPD 3.93, SD 0.01, p &lt; 0.01) and non-guideline-based antiemetics (aPPD -3.62, SD 0.006, p &lt; 0.01), were noted. Conclusions: The shock of the COVID-19 pandemic did not meaningfully change several metrics of low-value cancer care. Broader changes to payment and incentive design should be considered to turn the tide toward higher-value cancer care.
Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer
Authors: Esther H. Lips, Tapsi Kumar, Anargyros Megalios, Lindy L. Visser, Michael Sheinman, Angelo Fortunato, Vandna Shah, Marlous Hoogstraat, Emi Sei, Diego Mallo, Maria Roman-Escorza, Ahmed A. Ahmed, Mingchu Xu, Alexandra W. van den Belt-Dusebout, Wim Brugman, Anna K. Casasent, Karen Clements, Helen R. Davies, Liping Fu, Anita Grigoriadis, Timothy M. Hardman, Lorraine M. King, Marielle Krete, Petra Kristel, Michiel de Maaker, Carlo C. Maley, Jeffrey R. Marks, Brian A. Menegaz, Lennart Mulder, Frank Nieboer, Salpie Nowinski, Sarah Pinder, Jelmar Quist, Carolina Salinas-Souza, Michael Schaapveld, Marjanka K. Schmidt, Abeer M. Shaaban, Rana Shami, Mathini Sridharan, John Zhang, Hilary Stobart, Deborah Collyar, Serena Nik-Zainal, Lodewyk F. A. Wessels, E. Shelley Hwang, Nicholas E. Navin, P. Andrew Futreal, P. Andrew Futreal, E. Shelley Hwang, Jos Jonkers, None Jacco, Fariba Behbod, Daniel Rea, Proteeti Bhattacharjee, Donna Pinto, Ellen Verschuur, Marja van Oirsouw, Alastair M. Thompson, Jelle Wesseling, Elinor J. Sawyer
Journal: Nature Genetics (2022)

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.
LGG-62. Weight change in pediatric patients treated with MEK inhibitors: a retrospective cohort study
Authors: Hye Hyun Bahng, Jemily Malvar, Yueh-Yun Chi, Celia Framson, Nathan Robison
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: MEK inhibition is an emerging treatment strategy in pediatric tumors characterized by activation of the Ras-Raf-MEK-ERK pathway, including low-grade glioma (LGG) and neurofibromatosis 1 (NF1)-associated tumors. Preliminary clinical experience suggests that MEK inhibitors (MEKi) may be associated with weight gain in children, which has not been a reported toxicity in adults. METHODS: 35 patients &amp;gt; 1 and &amp;lt; 21 years old treated at CHLA with MEKi between October 2013 and May 2019 were identified. Data was collected at t = 0 (baseline), t = 3 months, t = 6 months, t = 12 months, and t = 24 months, as well as pre- and post-treatment time points. Weight change was categorized as no change (change in Z-score [-0.25, +0.25]), weight gain (change in Z-score &amp;gt; 0.25), and weight loss (change in Z-score &amp;gt; -0.25). RESULTS: Weight gain and weight loss were seen in 11 (34.4%) and 8 (25%) patients, respectively, after 6 months on therapy. Weight gain reversed in 4 out of 5 patients with post-treatment data. There was no clear association between weight outcome and hypothesized covariates (including hypothalamic location and NF1 status). Notably, significant weight gain was seen across baseline weight spectrum, including patients who had underweight and severely overweight BMI percentiles at baseline. CONCLUSION: Our findings preliminarily suggest that MEK inhibition may be associated with clinically significant weight change, especially weight gain, in a subset of children and young adults. Reversal upon drug cessation suggests a causal relationship. Further prospective and mechanistic investigation is needed.
Plasma methylated DNA markers of cutaneous melanoma: Association with PET/CT-positive disease.
Authors: Alexander Meves, William R. Taylor, Calise K. Berger, Douglas W. Mahoney, Kelli Burger, Enrica Quattrocchi, Karen A. Doering, Anna M. Gonser, Xiaoming Cao, Justin Heilberger, Brianna J. Gysbers, Patrick H. Foote, Viatcheslav E. Katerov, Hatim T. Allawi, John B. Kisiel
Journal: Journal of Clinical Oncology (2022)

9567 Background: Cutaneous melanoma surveillance is important to identify low-volume systemic disease, but imaging is costly and poorly accessible to patients; frequent skin checks lack sensitivity and specificity. We aimed to establish clinical feasibility of a liquid biopsy blood test, which quantifies validated, melanoma-specific, methylated DNA markers (MDMs), previously discovered, and reported by our team, using tissue extracted DNA. Methods: We prospectively collected blood from adult patients with histologically confirmed melanoma metastases and no other internal malignancies (within 5-years) who underwent surveillance by FDG-PET/CT (N = 88). Blood from age- and sex balanced cancer-free controls (N = 100) were compared. From PET/CT, we extracted the number of organs involved, SUV-max, and largest tumor diameter. Unequivocal metastasis was defined as SUV ≥ 4 and largest diameter &gt; 5 mm. Because PET/CT is inadequate for the screening of brain metastases, we excluded the brain from the analysis. MDMs ( chr11.149, HOXA9, chr20.210, FLJ22536, CLIC5, SIX4, chr7.155, chr17.730, chr1.110) were assayed using target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, in blinded fashion. Using a logistic regression approach and nine candidate MDMs, we calculated the sensitivity for detecting patients with metastasis on PET/CT at 100% specificity. Results: 52/88 (59%) of melanoma patients showed evidence of metastasis on PET/CT at the time of blood draw. At 100% specificity, a panel of 4 MDMs ( HOXA9, chr20.210, chr17.730, chr1.110) yielded a sensitivity of 86.5% (45/52 cases) vs. 100 cancer-free controls. When applying this model to the 36 PET/CT-negative patients, specificity was as high as 97.2% (35/36 cases) while maintaining a sensitivity of 86.5% (one patient with a positive test result had a complete metabolic response to binimetinib / encorafenib prior to negative PET/CT). For patients with ≥ 2 organs involved by metastasis, sensitivity was 100% (29/29 cases). False-negative cases had metastasis in single organs and were characterized by minimal tumor burden and oral corticosteroid use. One false-negative patient had localized stage III disease without known primary melanoma. Conclusions: Plasma MDM levels appear highly concordant with FDG-PET/CT in patients with metastatic cutaneous melanoma. A liquid biopsy approach has potential to lower cost and improve patient access to surveillance. Additional prospective studies in larger intended use cohorts are needed to validate our results.
Comparative effectiveness of different interventions for cancer-related fatigue delivered digitally by online platforms.
Authors: Paris A. Kosmidis, Elena Deligianni, Thanos Kosmidis
Journal: Journal of Clinical Oncology (2022)

1576 Background: As cancer treatments improve, patients’ quality of life becomes even more important. In parallel, supportive care delivery is increasingly challenging, also due to resource pressures and COVID19. The effectiveness of digital and remote patient support tools as a complementary approach to improve patients’ quality of life is under evaluation. Fatigue is considered among the most prevalent and persistent side effects regardless of tumour type; also, despite ongoing research, there is no single approach established. We compare the effectiveness of different self-care interventions delivered by online platforms to cancer patients in several countries. Methods: Patients report side effects (including Fatigue) on the CareAcross online platforms and receive tailored support to help them improve their quality of life. The supportive material encompasses many topics, and patients may receive several combinations. For Fatigue, different topics (nutrition, hydration, rest etc) were analysed to evaluate effectiveness based on prospectively collected patient reported outcomes. Results: 1456 breast, lung, colorectal or prostate cancer patients from 8 countries (mainly UK, Germany, France, Spain, Italy) reported Fatigue at least once. This analysis focuses on persistent fatigue: 1215 patients reported Fatigue more than once, receiving up to 7 permutations of topics (F1-F7; F4-7 consist of F1-3 combinations). All permutations include the “Physical Activity” topic (see Table). Overall, the “Hydration” topic stands out as consistently linked with the most effective material (all except F3). Comparative analysis between similar combinations shows that those with “Anemia warnings” and “Rest” tend to be more effective (F7&gt;F6). Ambiguously, the “Physical activity before &amp; after treatment”, “Relaxation exercises” and “Fatigue diary” topics contribute to effectiveness (F5&gt;F1), but do not counterbalance absence of the previous 3 (F1&gt;F3). Food-related topics have unclear impact, too: “Food types” is absent from the top combination (F2) where “Food timing” is used; however, that topic is linked with a slightly inferior combination (F7&gt;F5). Conclusions: Fatigue is a complex, multifactorial challenge; digitally delivered interventions can lower its incidence. Hydration appears effective, but the nature of these interventions complicates their thorough evaluation. Randomised studies may enhance these findings and enable additional personalisation towards further quality of life improvements. [Table: see text]
Incidence of Ischemic Stroke in Patients With Asymptomatic Severe Carotid Stenosis Without Surgical Intervention
Authors: Robert W. Chang, Lue-Yen Tucker, Kara A. Rothenberg, Elizabeth Lancaster, Rishad M. Faruqi, Hui C. Kuang, Alexander C. Flint, Andrew L. Avins, Mai N. Nguyen-Huynh
Journal: JAMA (2022)

Optimal management of patients with asymptomatic severe carotid stenosis is uncertain, due to advances in medical care and a lack of contemporary data comparing medical and surgical treatment.To estimate stroke outcomes among patients with medically treated asymptomatic severe carotid stenosis who did not undergo surgical intervention.Retrospective cohort study that included 3737 adult participants with asymptomatic severe (70%-99%) carotid stenosis diagnosed between 2008 and 2012 and no prior intervention or ipsilateral neurologic event in the prior 6 months. Participants received follow-up through 2019, and all were members of an integrated US regional health system serving 4.5 million members.Imaging diagnosis of asymptomatic carotid stenosis of 70% to 99%.Occurrence of ipsilateral carotid-related acute ischemic stroke. Censoring occurred with death, disenrollment, or ipsilateral intervention.Among 94 822 patients with qualifying imaging studies, 4230 arteries in 3737 (mean age, 73.8 [SD 9.5 years]; 57.4% male) patients met selection criteria including 2539 arteries in 2314 patients who never received intervention. The mean follow-up in this cohort was 4.1 years (SD 3.6 years). Prior to any intervention, there were 133 ipsilateral strokes with a mean annual stroke rate of 0.9% (95% confidence interval [CI], 0.7%-1.2%). The Kaplan-Meier estimate of ipsilateral stroke by 5 years was 4.7% (95% CI, 3.9%-5.7%).In a community-based cohort of patients with asymptomatic severe carotid stenosis who did not undergo surgical intervention, the estimated rate of ipsilateral carotid-related acute ischemic stroke was 4.7% over 5 years. These findings may inform decision-making regarding surgical and medical treatment for patients with asymptomatic severe carotid artery stenosis.
Relationship between nocturia and sleep problem in cross-sectional and longitudinal analysis: The Nagahama study
Authors: H. Negoro, A. Fukunaga, K. Setoh, T. Kawaguchi, S. Funada, T. Yoshino, K. Yoshimura, H. Nishiyama, Y. Tabara, F. Matsuda, O. Ogawa
Journal: European Urology (2022)